insulin secretion and action Flashcards
what is the normal range for fasting glucose?
3.5-5.5mmol/L
what are the main roles of insulin?
- High glucose levels -Removal of glucose from blood (transport)
- Synthesis of glycogen and triglycerides (to store energy)
- Inhibition of processes that release glucose/fatty acids
what happens in low glucose when insulin secretion is inhibited?
- Low glucose levels –No glucose transport
- Glycogen and triglycerides are not synthesised anymore
- Processes that release glucose/fatty acids are not inhibited anymore
what is the main hormone controlling blood glucose levels during fasting?
glucagon
how many amino acids in a glucagon peptide?
29
describe how the synthesis of glucagon occurs
preproglucagon –> proglucagon –> pancreatic a-cells
or proglucagon can also undergo post-translational processes –> L-intestinal cells in the brain
what stimulates glucagon secretion?
- Low blood glucose levels – normal fasting levels of glucose: 80-90mg/100ml
- Increased blood amino acids – especially alanine and arginine
- Exercise – in exhaustive exercise blood conc of glucagon increases 4.5 fold
- Increase in intracellular calcium triggers an increase in glucagon
what inhibits glucagon secretion?
insulin
somatostatin
what type of receptor is the glucagon receptor?
GPCR - 7 transmembrane domains
explain how glucagon activates the receptor?
- Dissociation of the trimer upon ligand binding to the receptor activates the signalling cascade - In the absence of glucose, trimer is assembled
- When glucagon binds, a-subunit dissociates and can activate a cyclase - makes cAMP
- cAMP triggers activation of the cascade
- Activates PKA which activates phosphorylase
- Only when the ligand binds, there’s production of cAMP
how can insulin regulate glucagon signalling?
- Further regulation by insulin: insulin can switch glucagon-dependent signalling off
- Insulin can break down cAMP to 5’ AMP by activating phosphodiesterase
describe metabolism during fasting?
- Reduced glucose levels – no insulin secretion
- Glycogenolysis isn’t inhibited
- No glucose transport
- Glycogen and triglycerides are not synthesised anymore
- Processes that release glucose/fatty acids are NOT INHIBITED
- Liver releases glucose into the bloodstream
- Gluconeogenesis – synthesis of new glucose – is stimulated by glucagon in the liver
- Lipolysis is not inhibited by insulin
how does glucagon increase gluconeogenesis and inhibit glycolysis in the liver?
- Increases amino acid uptake by liver cells
- Inhibition of PFK-1 (mediated by cAMP/PKA)
- Inhibition of pyruvate kinase (mediated by cAMP/PKA)
what is lipolysis?
breaking down of triglycerides to FFAs and glycerol
what effect does HSL have on lipolysis?
increases lipolysis
what inhibits and activates HSL?
HSL inhibited by insulin and activated by glucagon/PKA
what effect does malonyl-CoA have on beta oxidation?
• Malonyl-CoA inhibits transport of FFAs into the mitochondria by CPT-1 therefore inhibiting B-oxidation
what effect does glucagon have on CPT-1?
stimulates it
how do ketone bodies form during fasting?
Accumulation of Acetyl-CoA that can’t enter TCA cycle is converted into KETONE BODIES
when are catecholamines released?
Short term stress response - Released in response to stress and hypoglycaemia
what are catecholamines?
Monoamines synthesised from phenylalanine and tyrosine
what effect do catecholamines have?
• Increase HR and BP, causes liver to convert glycogen to glucose, dilation of bronchioles etc
which cells secrete glucocorticoids and other steroids?
cortex cells
how are cortex cells adapted for steroid hormone synthesis?
have many LDL receptors which enables cholesterol uptake
what stimulates cortisol release?
secreted in response to adrenocorticotropic hormone (ACTH) from the pituitary - -ve feedback loop
what effects do cortisol have on metabolism?
- Enhances gluconeogenesis
- Inhibits glucose uptake and utilisation
- Stimulates muscle proteolysis
- Stimulates adipose-tissue lipolysis rapid mobilisation of amino acids and fatty acids from cellular stores
what is the role of cortisol in stress and inflammation?
- Cortisol is important in resisting stress and inflammation e.g. from trauma, infection, intense heat or cold, surgery or almost any debilitating disease
- Helps maintain BP and it supresses inflammation
what can happen if cortisol levels are elevated for a prolonged time?
can induce proteolysis and muscle wasting
what are thyroxine (T4) and Triiodothyronine (T3) ?
iodinated thryonines
what do T3 and T4 do?
• Activate nuclear receptors and transcription of large number of genes
which is more potent? T3 or T4?
T3 is about 4 times more potent than T4
which is present in smaller quantities - T3 or T4?
T3
what are the metabolic actions of thyroid hormones?
- increase in the number and activity of the mitochondria
- stimulation of carbohydrate metabolism
- stimulation of fat metabolism
- leads to increased basal metabolic rate
how do thyroid hormones stimulate carbohydrate metabolism?
o Rapid glucose uptake
o Enhanced glycolysis and gluconeogenesis
o Increased insulin secretion
how is fat metabolism stimulated?
o Lipid mobilised rapidly from fat tissue
o Increased fatty acids concentration in the plasma
what are incretins?
group of GI hormones
what are the functions of GLP-1?
o Inhibits glucagon secretion and hepatic glucose production
o Augments glucose-induced insulin secretion
o Slows gastric e,ptying
o Promotes satiety
o Increases insulin biosynthesis
o Promotes B-cell differentiation
what can cause hypoglycaemia?
o High insulin doses
o Alcohol excess – inhibits gluconeogenesis
o Insulinoma – tumour of pancreatic B cells
o Excessive exercise – leading to increased glucose utilisation
o Reactive hypoglycaemia – excessive insulin secretion in response to a high carbohydrate meal in pre-diabetic condition
what are symptoms of hypoglycaemia?
- Confusion, disorientation, convulsion, fitting, seizures, loss of consciousness, coma
- Autonomic symptoms
- Neuroglycopaenic symtpoms; difficulty concentrating, confusion, weakness, drowsiness, vision changes, difficulty speaking, dizziness, tiredness
- Autonomic symptoms; Trembling, palpitation, sweating, anxiety, hunger, tingling
what is secreted in prolonged hypoglycaemia?
• Growth hormone and cortisol are secreted – decrease rate of glucose utilisation
what are the consequences of prolonged hypoglycaemia?
o Neuroglycopaenia – shortage of glucose for the brain
o Prolonged and repeated hypoglycaemia may produce permanent brain damage
o Loss of cognitive function, seizures and coma
what can cause severe hypoglycaemia?
• Can occur in patients using blood glucose lowering medication or prandial glucose regulators as a result of;
o Missed or delayed meal
o Overdose medication
o Exercise (without adjustment in medication)
o Alcohol assumption
